Breast cancer (BC) is the most commonly diagnosed cancers in women, and approximately 2.5 million American women with a personal history of breast cancer are alive today. Late stage cancer comes with a high risk of mortality, making BC the second leading cause of cancer-related deaths in women in the US. Despite major advances in screening and detection, BC is still a major killer of women and the identification of novel pathways to combat BC is urgently needed. The Ron receptor is overexpressed in ~50% of human BC and is an independent predictor of metastases and poor prognosis in women with this disease. While Ron overexpression is an important factor in human BC and metastasis, a significant gap exists in our knowledge about the mechanisms by which Ron promotes the development of aggressive disease. To examine Ron further, transgenic mice were generated that produce mammary-specific Ron overexpression. These mice, referred to as the MMTV-Ron mice, mimic the aggressive disease pattern observed in human patients with all female mice developing highly metastatic breast tumors. In this clinically relevant model, we discovered that mammary tumors upregulate the Ron ligand, hepatocyte growth factor-like protein (HGFL), despite the presence of this growth factor in the circulation. Utilizing MMTV-Ron mice deficient in HGFL, our preliminary studies show the importance of HGFL for oncogenic Ron activation and mammary tumor growth and progression. Utilizing HGFL deficient mammary tumor cells, we show that reconstitution of HGFL promoted tumor cell autonomous survival, migration and invasion. Further, we show that global HGFL loss also dramatically affected the tumor microenvironment by regulating immune cell recruitment, macrophage polarization, breast cancer stem-like cell/tumor initiating cell (BCSC) numbers, and angiogenesis. Analysis of bone marrow derived macrophages shows that HGFL augments Stat3 activation and promotes the expression of markers of alternative macrophage activation, supporting a role for HGFL-induced Ron signaling in suppressing anti-tumor immune responses. These studies are further supported by recent reports showing that Ron signaling in myeloid cells, and specifically in macrophages, is critical for suppressing cytotoxic T-cell responses and promoting tumor growth. Combined, these data support both tumor cell intrinsic and extrinsic functions for HGFL-induced Ron activation in promoting mammary tumor growth and metastasis. In this revised renewal application, we will directly define the functions of the Ron signaling pathway in macrophages and epithelial cells during breast tumorigenesis and will examine the significance of tumor cell produced HGFL in directing tumor growth and immunosuppression through autocrine and paracrine signaling. We will test the hypothesis that tumor cell produced HGFL promotes aggressive BC through the cooperative activation of myeloid and epithelial Ron signaling within the tumor microenvironment. To test this hypothesis, three Specific Aims are proposed: (i) to elucidate the mechanism(s) by which myeloid Ron signaling augments breast tumor growth; (ii) to determine the source and mechanism by which HGFL supports BC growth and metastasis, and (iii) to define the function of tumor cell-specific Ron expression in promoting breast tumorigenesis. In total, we hope to understand the role of the HGFL-Ron signaling axis in the development and spread of BC and provide a rationale for new diagnostic or treatment modalities that target both the tumor proper and immune response to mitigate BC mortality.